CN104220062A - (3s,3s’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)和第二抗高血压药的组合 - Google Patents
(3s,3s’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)和第二抗高血压药的组合 Download PDFInfo
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- CN104220062A CN104220062A CN201280069935.4A CN201280069935A CN104220062A CN 104220062 A CN104220062 A CN 104220062A CN 201280069935 A CN201280069935 A CN 201280069935A CN 104220062 A CN104220062 A CN 104220062A
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Abstract
本发明涉及一种药物组合物,其在至少一种可药用的载体或赋形剂中包含(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)或其可药用的盐或溶剂合物和选自血管紧张素I转换酶抑制剂(ACEIs)和血管紧张素II 1型受体拮抗剂的第二活性成分的组合。所述组合物特别可用于治疗高血压和相关疾病与病症。
Description
发明领域
本发明涉及一种药物组合物,其在至少一种可药用的载体或赋形剂中包含(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)或其可药用的盐或溶剂合物和选自血管紧张素I转换酶(EC 3.4.15.1)抑制剂(ACEIs)和血管紧张素II1型受体(AT1R)拮抗剂的第二活性成分的组合。所述组合物特别可用于治疗高血压和相关疾病与病症。
技术背景
高血压是其原因通常仍未知的一种动脉疾病。可能参与的外在因素包括肥胖、缺乏锻炼的生活方式、过量饮酒或摄入盐,以及压力。提议发挥作用的内在因素包括液体潴留、交感神经系统活性和血管收缩。动脉高血压可以直接或间接导致心脏、周围血管系统和心脑血管系统、大脑、眼睛和肾脏的疾病。血糖控制和/或降低血压(BP)是预防糖尿病并发症如肾病、视网膜病和神经病变的主要治疗策略。
抗高血压药已经广泛用于治疗高血压和相关疾病与病症。
尽管可以使用超过75种抗高血压药,在普通人群中的BP控制及其相伴的风险因素仍难以控制。事实上,65%的确诊为高血压的患者并不具有受控的高BP(<140/90mmHg)。许多患者需要超过一种药物以成功实现他们的目标BP水平,在许多情况下开出两种或甚至三种药物组合的处方。目前的抗高血压药在非洲裔患者或患有糖尿病或肾功能不全(其高BP与低血浆肾素水平和高血浆精氨酸升压素(AVP)水平相关)的患者中也不那么有效。最后,对至少三种抗高血压药(包括利尿剂)的耐药性高血压的总发病率估计为高血压人口的15%。因此,存在未满足的医疗需求以开发具有不同作用机制的新的抗高血压疗法作为替代或补充疗法以进一步改善患者的BP控制和相关心血管风险。
抗高血压药降低血压BP,尽管不同组中作用机理相差巨大。在该治疗分类中,存在几个亚类,包括非常大量的药物,其中尤其在下文中列举药物,这些药物是代表性的但是并非是其分类中仅有的成员。动脉高血压的治疗包括使用噻嗪类利尿剂、β-肾上腺素能阻断剂(“β阻滞剂”)、α/β-肾上腺素能阻断剂、非特异性肾上腺素能阻断剂、血管紧张素转换酶抑制剂(ACEIs)、AT1R拮抗剂(或血管紧张素II 1型受体阻断剂[ARBs])、钙通拮抗剂或阻滞剂(CCBs)和直接血管扩张剂。
噻嗪类利尿剂包括氯噻嗪、氢氯噻嗪(或HCTZ)、氯噻酮、吲达帕胺、多噻嗪和氢氟噻嗪。该分类中的药物经几种机理降低BP。通过促进钠流失,它们降低血容量。同时,降低了血管壁压力和外周血管阻力。噻嗪类利尿剂通常用作降低轻度高血压的首选,并通常与其它抗高血压药组合使用。特别地,氢氯噻嗪以及较小程度的氯噻酮与特定ACEIs、ARBs、β阻滞剂和其它利尿剂的组合目前是用于抗高血压的可用组合。
理想的是识别进一步的组合以治疗动脉高血压。
ACEIs通过已知血管紧张素II的产生来起作用,血管紧张素II是一种肽物质,其通过作用于AT1受体来诱发血管收缩和钠滞留,导致水潴留和提高的血容量。存在许多目前可以在市场上获得的ACEIs,包括卡托普利、雷米普利、喹那普利、依那普利、培哚普利和贝那普利。这些药物之间的主要差别在于它们起作用的开始与持续时间。
ARB类,如氯沙坦、坎地沙坦、厄贝沙坦、替米沙坦、缬沙坦、奥美沙坦和依普罗沙坦阻断血管紧张素II对AT1受体的作用而非阻断其生产(如ACEIs)。
ACEIs和ARBs由此通过经由ACE抑制作用防止其形成或通过防止血管紧张素II结合到AT1受体来针对全身肾素-血管紧张素系统(RAS),更特别针对血管紧张素II。在两种情况下,抑制导致血管扩张和BP降低。
最近的证据支持在大脑中也存在功能性RAS,其控制心血管功能和体液平衡(Llorens-Cortes C.and Mendelsohn FA.Organisation and functional role ofthe brain angiotensin system.J Renin Angiotensin Aldosterone Syst 2002年9月;3Suppl 1:S39-S48)。脑RAS且特别是氨基肽酶A(APA)——分别涉及体内脑血管紧张素II(AngII)和血管紧张素III(AngIII)(Zini等人PNAS1996)的膜结合锌金属蛋白酶——的过度活跃在各种高血压动物模型中调节高血压方法起到了至关重要的作用(Marc Y.and Llorens-Cortes C.The role ofthe brain renin-angiotensin system in hypertension:Implications for new treatment.Prog Neurobiol.2011年7月7日;95(2):89-103)。一些研究指出,在大脑中,AngIII而非在神经末梢周围建立的Ang II构成了在BP控制和AVP释放方面脑RAS主要效应肽之一(Zini等人PNAS1996,Reaux等人PNAS 1999)。此外,脑AngIII对于在高血压动物体内控制BP起到了紧张性刺激作用(Reaux等人PNAS 1999,Fournie-Zaluski等人PNAS 2004)。因此,脑APA,在脑RAS中生成AmgIII的酶,构成了治疗动脉高血压的治疗目标,中枢活性APA抑制剂代表了新一类抗高血压药。在这些新型抗高血压药中,特别可以提及(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸),其是选择性氨肽酶A(APA)抑制剂3-氨基4-巯基丁烷磺酸(也称为EC33)的前药。
除了在使用可用的整套药物治疗的高血压患者体内改善BP控制之外,流行病学研究支持了对开发新一类抗高血压药如(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)和新药物组合的需要,所述新一类抗高血压药和新药物组合可以干扰涉及在不受控制和/或耐药性患者体内高BP的发生和维持的机理,与现有治疗相比表现出降低的副作用并降低了心血管疾病如心肌梗死、心跳停止、中风或肾功能不全的相关风险。
发明概述
发明人确定了能获得显著降压效果的极有前途的药物组合。更特别地,这种显著的降压效果在口服抗高血压药后早期(特别是小于2小时)发生并以令人满意的方式保持。
在一个实施方案中,本发明涉及一种药物组合物,其在至少一种可药用的载体或赋形剂中包含(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)或其可药用的盐或溶剂合物和选自ACEIs与ARBs的第二活性成分的组合。
所述组合物特别可用于治疗动脉高血压或间接或直接相关疾病。
根据本发明的另一实施方案,公开了用于治疗高血压和间接或直接相关疾病的方法。该方法和本发明的用途包括向需要此类治疗的对象施用有效量的药物组合物,所述药物组合物在至少一种可药用的载体或赋形剂中包含(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)或其可药用的盐或溶剂合物和选自ACEIs与ARBs的第二活性成分的组合。
发明描述
该ACEIs更特别包括赖诺普利、依那普利、喹那普利、雷米普利、贝那普利、卡托普利、西拉普利、福辛普利、咪达普利、莫昔普利、群多普利和培哚普利。根据一个优选实施方案,该ACEI选自依那普利、卡托普利、雷米普利和喹那普利。更具体而言,该ACEI是依那普利。
该ARBs更特别包括氯沙坦、坎地沙坦、厄贝沙坦、替米沙坦、缬沙坦、奥美沙坦和依普罗沙坦。根据一个优选实施方案,该ARB选自氯沙坦、坎地沙坦、缬沙坦和奥美沙坦。更具体而言,该ARB是缬沙坦。
(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)是选择性氨基肽酶A(APA)抑制剂3-氨基4-巯基丁烷磺酸(也称为EC33)的二聚物,通常通过在两个3-氨基4-巯基丁烷磺酸分子的硫醇基之间产生二硫键而生成。二聚化提供了更容易穿过肠胃和血-脑屏障的分子作为前药。(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)(也称为RB150)已经证实是有效的抗高血压药,如Fournie-Zaluski等人PNAS 2004和Bodineau等人在Hypertension 200851,1318-1325中描述的那样。
(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)及其作为抗高血压药的用途已经公开在专利申请WO 2004/007441中。
还可以使用其可药用的盐或溶剂合物。
事实上,有机化合物可以与溶剂形成复合物,在该溶剂中它们反应,或它们从该溶液中沉淀或结晶。这些复合物称为“溶剂合物”。例如,与水的复合物称为“水合物”。(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)的溶剂合物在本发明的范围内。有机化合物可以以超过一种结晶形式存在。例如,各溶剂合物的结晶形式可能不同。由此(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)或其可药用的溶剂合物的所有结晶形式在本发明的范围内。
本领域技术人员还要理解的是,(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)还可以以其可药用盐的形式使用。(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)的可药用盐包括由可药用的无机或有机酸或碱形成的常规盐以及季铵盐。合适的酸式盐的更具体的实例包括盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、双羟萘酸盐(palmoic)、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟萘甲酸、氢碘酸、苹果酸、steroic、鞣酸等等。其它酸如草酸,虽然本身不可药用,但可用于制备可用作获得本发明化合物及其可药用盐的中间体的盐。合适的碱式盐的更具体实例包括钠、锂、钾、镁、铝、钙、锌、N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因的盐。下文中提到(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)包括酸形式及其可药用的盐和溶剂合物。
在优选的实施方案中,与高血压间接或直接相关的疾病选自心脏、周围血管系统和心脑血管系统、大脑、眼睛和肾脏的疾病。特别地,疾病包括原发性和继发性动脉高血压、猝发、心肌缺血、心衰竭、肾衰竭、心肌梗死、周围血管疾病、糖尿病蛋白尿、X综合征和青光眼。其还可以更特别包括高血压糖尿病患者的肾病、视网膜病和神经病变。
在本发明的情况下,术语治疗是指根治治疗、症状治疗和预防治疗。本发明的组合物可用于患有现有高血压的人类。本发明的组合物不一定能够治愈患有高血压的患者,但是可以以令人满意的方式控制BP,由此延迟或减缓其进展,或由此进一步预防高血压的并发症,如上述的直接或间接疾病。这将会因此改善患者的病情。本发明的组合物还可以施用于那些不具有间接或直接疾病但是通常会发展此类疾病或具有提高的所述疾病风险的患者,它们将不会发展所述疾病。治疗还包括在因年龄、家族史、遗传或染色体异常而最终将发展所述疾病或具有所述疾病风险的个体中延缓间接或直接疾病的发展。通过延缓间接或直接疾病的开始,本发明的组合物在其中该个体通常已罹患该疾病的时期内防止该个体罹患该疾病,或施用本发明的组合物直到该个体最终罹患该疾病为止降低了疾病或其某些效果的发展速率。
在治疗高血压时,本发明的组合物以治疗有效量施用。
在本发明的一个方面,(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)和第二抗高血压药的量足以产生协同降压作用。
在更优选的实施方案中,该第二抗高血压药是如上文定义的ACEI。
本发明的药物组合物可用于治疗高血压或间接或直接相关疾病。
本发明的药物组合物有利地含有一种或多种可药用的载体或赋形剂。更优选地,该组合物意在口服,该可药用的载体或赋形剂由此适于口服。作为实例,可以提及与药物用途相容并且是本领域技术人员已知的盐水、生理学溶液、等渗溶液、缓冲溶液等等。
包含活性成分,即(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)或其可药用的盐或溶剂合物和选自ACEIs与ARBs的第二活性成分的组合的药物组合物可以通过将活性成分一起全部或单独地与生理可接受的载体、赋形剂、粘合剂或稀释剂等等混合在一起来制备。本发明的药物组合物更具体用于同时、单独或顺序施用所述活性成分,优选用于同时施用所述活性成分。
该药物组合物随后口服施用或非口服施用,例如经由胃肠外、静脉内、皮肤、经鼻、直肠途径或经由气溶胶输送至肺。如果活性成分独立配制,相应制剂可以使用例如稀释剂临时混合在一起并随后施用,或者可以彼此独立地、连续或顺序地施用。
优选地,本发明的组合物口服施用。
本发明的药物组合物包括制剂,如颗粒、粉剂、片剂、凝胶胶囊、糖浆、乳剂和混悬剂,以及用于非口服施用的形式,例如注射剂、喷雾剂或栓剂。
该药物剂型可以经由已知的常规技术来制备。
口服固体药物剂型的制备将通过下列方法进行:将赋形剂(例如乳糖、蔗糖、淀粉、甘露醇等)、崩解剂(例如碳酸钙、羧甲基纤维素钙等)、粘合剂(例如淀粉、阿拉伯胶、羧甲基纤维素、聚乙烯基吡咯烷酮、羟丙基纤维素等)和润滑剂(例如滑石、硬脂酸镁等)例如添加到该活性成分中并随后将获得的混合物压片。如果需要的话,可以经由已知技术将该片剂包衣以掩盖味道(例如用可可粉、薄荷等)或允许活性成分的肠溶或持续释放。可以添加可药用着色剂。药物剂型如片剂、粉剂、囊剂和凝胶胶囊可用于口服。
用于口服的液体药物剂型包括溶液、混悬剂和乳剂。可以通过在水中溶解该活性成分并随后在必要时添加调味剂、着色剂、稳定剂和增稠剂来获得该水溶液。为了改善溶解度,可能加入乙醇、丙二醇或其它可药用的非水性溶剂。用于口服施用的水性混悬剂可以通过用粘性产品如天然或合成树胶、树脂、甲基纤维素或羧甲基纤维素钠将细碎的活性成分分散在水中来获得。
可以通过例如下列方法获得用于注射的药物剂型。将该活性成分与分散剂、防腐剂、等渗剂以及其它添加剂如在需要的情况下的增溶剂或稳定剂一起溶解、悬浮或乳化在水性介质(例如蒸馏水、生理盐水、林格氏溶液等)或在油性介质(例如植物油,如橄榄油、芝麻油、棉籽油、玉米油等,或丙二醇)中。
可以由含有该活性成分的固体、半固体或液体组合物获得用于外用的药物剂型。例如,为了获得固体剂型,将活性成分单独或混合地与赋形剂和增稠剂一起处理以将其转化为粉末。液体药物组合物以与如前所述的注射剂型基本相同的方式制备。半固体药物剂型优选为水性或油性凝胶形式或为香膏剂形式。这些组合物可以任选含有pH调节剂以及其它添加剂。
由本领域技术人员确定本发明的组合物或活性成分的治疗有效量(即有效剂量)。更具体而言,有效量是能够降低和保持BP以控制BP,特别是建议<140/90毫米汞柱的BP目标的量。更优选地,(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)和第二抗高血压药的量足以产生协同降压作用。本发明的组合物可以每周施用至少一次,但也可以每天一次或每2、3、4、5或6天一次。
此外,要理解的是,用于治疗所需的本发明的活性成分的量将随着待治疗的病症的性质以及对象的年龄与条件而改变,并最终取决于主治医生或兽医。但是,通常,用于成人治疗的剂量通常为每天或每隔一天0.02-5000毫克,优选每天或每隔一天1-1500毫克的(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)。对于第二抗高血压药,用于成年人治疗的剂量将考虑其推荐剂量。所需剂量将方便地以单一剂量或以适当间隔敷用的分次剂量(例如每天或每隔一天的两个、三个、四个或更多个分剂量)呈现。本发明的组合物对于片剂和胶囊可以含有0.1-99%的各活性成分,方便地为30-95%,对于液体制剂为3-50%。
活性成分的相对比例可以根据对象条件和根据第二所选活性成分而改变。例如,(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)相对于依那普利的重量比可以为10/1至300/1,优选为25/1至200/1。(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)相对于缬沙坦的重量比可以为5/1至500/1,优选为10/1至200/1。施用本发明的活性成分的频率优选为每天或每隔一天施用一次到两次。
根据本发明,对象可以是人类或动物。
本发明的目的还在于提供如上定义的方法或组合物,其中共同施用两种活性成分。本发明涉及经由共同施用有效量的(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)或其可药用的盐或溶剂合物和选自ACEIs与ARBs的第二活性成分进行治疗的如上定义的方法或组合物,以及允许这种共同施用的试剂盒。
本发明还涉及适于通过上述方法进行治疗的试剂盒。这些试剂盒包含含有(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)或其可药用的盐或溶剂合物的组合物和含有选自ACEIs与ARBs的第二活性成分的第二组合物,以便同时、单独或顺序施用,优选用于同时施用。
该药物组合物可以与施用说明书一起包含在容器、包装或分配器中。
术语“共同施用”指的是经最多2小时或甚至最多6小时的时段向同一对象或患者同时、单独或顺序施用两种活性成分。例如术语共同施用包括(1)同时施用两种活性成分,(2)施用第一活性成分,接着在2小时后施用第二活性成分,(3)施用第一活性成分,接着在6小时后使用第二活性成分。
根据一个优选实施方案,两种活性成分同时共同施用。
附图说明
图1:通过口服途径单独或组合给出的RB150和依那普利对警戒自发性高血压大鼠(急性期治疗)的BP的效果——p<0,05vs RB150;*p<0,05vs依那普利;对于依那普利和依那普利+RB150,n=4,对于RB150,n>7。
图2:在口服RB150或依那普利后清醒SHR的平均动脉血压(MABP)变化。在服药(B)后在不同时间处在清醒小鼠体内在紧急口服RB150(15-150毫克/千克)或依那普利(3毫克/千克)后在平均动脉BP的峰值变化(ΔMABP,以毫米汞柱为单位,平均值±SEM)。非配对t检验,*P<0.05;**P<0.01;***P<0.001vs在口服生理盐水后在SHR中获得的相应MABP值的变化。
图3:在紧急口服单独或组合给出的RB150(100毫克/千克)或缬沙坦(1毫克/千克)后在清醒小鼠体内的平均动脉血压(MABP)变化。在服药后不同时间处(对每剂量的n=3至5)的MABP的峰值变化(ΔMABP,以毫米汞柱为单位,平均值±SEM)。
图4:在紧急口服单独或组合给出的RB150(100毫克/千克)或缬沙坦(0.3毫克/千克)后在清醒小鼠体内的平均动脉血压(MABP)变化。在服药后不同时间处(对每剂量的n=3)的MABP的峰值变化(ΔMABP,以毫米汞柱为单位,平均值±SEM)。
给出本发明的组合物的下列实例作为非限制性例示。
实施例
除非另行说名,量基于重量表示。
材料和方法
活性成分
将RB150、ACEI、依那普利(由Merck Sharp and Dohme research Lab提供)和ARB、缬沙坦(Sigma-Aldrich)溶解在无菌盐水中并调节至pH 7.4用于体内施用。
动物
雄性自发性高血压大鼠(SHR),称重250至350克,获自Charles RiverLaboratories(L’Arbresle,France),并将动物关在人造光源下(12小时光照/12小时黑暗周期),给予正常饮食标准,水无限供应。根据National Institutes ofHealth Guide for the Care and Use of Laboratory Animals进行试验。
外科方法和血压记录
十二周雄性SHR用戊巴比妥钠(60毫克/千克,腹膜内,Centravet)麻醉。在股动脉中植入导管。股动脉导管在皮肤下输送并在颈背处出现。在手术后,各大鼠给予腹膜内注射0.1毫升青霉素-链霉素(50,000单位/毫升;Sigma)并在试验前令其恢复至少24小时。通常,在清醒的、自由活动的小鼠中经口施用盐水、RB150(100毫克/千克)或依那普利(1毫克/千克)或缬沙坦(0.3毫克/千克)。例如,为了制备口服溶液,首先将RB150加依那普利、RB150和依那普利在无菌盐水中分别稀释至15毫克/毫升和6毫克/毫升。随后对称重为300克的大鼠,将0.05毫升的依那普利(6毫克/毫升)与2毫升的RB150(15毫克/毫升)混合,并将通过管饲法将2毫升最终溶液口服给予SHR。在治疗后,在试验的第一天连续监控动脉血压(MABP)和心率(HR)6小时。在给药后24小时进行另一次1小时记录。通过使用连接到由MacLab硬件单元和在Macintosh计算机上运行的图表软件组成的MacLab系统(Phymep)上的COBE CDX III压力传感器监控各试验。通过BP信号计算MABP和HR。
数据分析和统计
对口服RB150后的MABP与HR进行配对或非配对t检验。进行方差的阶乘双向分析(ANOVA)以测试时间和治疗对ΔMABP的不同变量的相互作用。通过阶乘单因素方差分析和Fisher PLSD测试在每个时间处比较各次治疗中的治疗组和盐水组。如果P值<0.05,则被认为差异显著。
结果
联合紧急口服RB150与依那普利对自由运动的SHR的BP与HR的作用
在清醒的SHR中,联合口服RB150(100毫克/千克)与依那普利(1毫克/千克)显著和引人注意地降低了MABP(图1),而没有显著改变HR(未显示)。在施用后一小时,BP的降低(-24±2.9毫米汞柱)已经非常明显(图1)。在使用后6小时观察到MABP的最大降低(-42±3.6毫米汞柱)。对每个时间,RB150(100毫克/千克,po)加依那普利(1毫克/千克,po)的组合引发的降压效果明显不同于单独施用的各化合物的降压效果。这在给药后一小时特别明显。事实上,在服药后1小时,甚至更高剂量的单独的RB150(即150毫克/千克,口服)或依那普利(即3毫克/千克,口服)也没有在SHR中引发任何显著的BP降低(图2)。
联合紧急口服RB150与缬沙坦对自由运动的SHR的BP与HR的作用
在清醒的SHR中,相伴口服RB150(100毫克/千克)与缬沙坦(1毫克/千克)显著降低了MABP(图3)。但是在该剂量的缬沙坦下,由该组合引发的BO降低并未显著不同于单独施用的各化合物引发的BO降低。有趣的是,联合口服RB150(100毫克/千克)与较低剂量的缬沙坦(即0.3毫克/千克)也在清醒SHR中显著降低了MABP(图4)。在施用后4至6小时之间观察到最大BP降低(-40至-45毫米汞柱)。在施用后4至6小时之间,通过RB150(100毫克/千克,口服)和缬沙坦(0.3毫克/千克)的组合引发的降压效果不同于单独施用的各化合物的降压效果。这在施用后4小时特别明显。表明RB150与缬沙坦的组合可以改善BP控制,同时减少缬沙坦的剂量。
配制实施例:
可以制备以50/1重量比混合(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)和依那普利的下列药物组合物用于治疗单位制剂。该药物组合物可以调节至玻璃小瓶中。粉末在口服使用前临时用100毫升水重构。
组分 | 比50:1 |
RB150 | 125.00毫克 |
依那普利 | 2.50毫克 |
乳糖,无水 | 202.70毫克 |
硬脂酸镁 | 3.38毫克 |
二氧化硅,牙科类型 | 6.76毫克 |
每瓶总量 | 340.34毫克 |
该药物组合物可以如下制备:使用800微米筛将RB150和二氧化硅筛分,随后使用X袋(或同等材料)在3rpm下混合5分钟。依那普利马来酸盐和无水乳糖随后加入,在3rpm下持续混合10分钟,在5分钟后反转。加入硬脂酸镁,在3rpm下进行混合2分钟。小瓶用计算量的最终混合物装满以获得含有125毫克的RB150和2.5毫克的依那普利的小瓶。
可以制备相同同类的包含RB150与缬沙坦的药物组合物。
Claims (11)
1.药物组合物,其在至少一种可药用的载体或赋形剂中包含(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)或其可药用的盐或溶剂合物和选自血管紧张素转换酶抑制剂和血管紧张素II 1型受体拮抗剂的第二活性成分的组合。
2.根据权利要求1所述的药物组合物,其中该血管紧张素转换酶抑制剂选自依那普利、卡托普利、雷米普利和喹那普利。
3.根据权利要求1或2所述的药物组合物,其中该血管紧张素转换酶抑制剂是依那普利。
4.根据前述权利要求任一项所述的药物组合物,其中该血管紧张素II 1型受体拮抗剂选自氯沙坦、坎地沙坦、缬沙坦和奥美沙坦。
5.根据权利要求1或4所述的药物组合物,其中该血管紧张素II 1型受体拮抗剂是缬沙坦。
6.根据前述权利要求任一项所述的药物组合物,其中该可药用的载体或赋形剂适于口服。
7.根据权利要求3所述的药物组合物,其中(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)相对于依那普利的重量比为25/1至300/1,优选为50/1至200/1。
8.根据权利要求5所述的药物组合物,其中(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)相对于缬沙坦的重量比为5/1至500/1,优选为10/1至200/1。
9.根据前述权利要求任一项所述的药物组合物,用于治疗动脉高血压或间接或直接相关疾病,尤其是心衰竭。
10.根据权利要求7或8所述的药物组合物,其中两种活性成分共同施用,优选同时共同施用。
11.试剂盒,包含含有(3S,3S’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)或其可药用的盐或溶剂合物的组合物和含有选自血管紧张素转换酶抑制剂与血管紧张素II 1型受体拮抗剂的第二活性成分的第二组合物,用于同时、单独或连续施用,优选用于同时施用。
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CN201280069935.4A Expired - Fee Related CN104220062B (zh) | 2011-12-21 | 2012-12-21 | (3s,3s’)4,4’-二硫烷二基双(3-氨基丁烷1-磺酸)和第二抗高血压药的组合 |
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FR2858617A1 (fr) * | 2003-08-06 | 2005-02-11 | Inst Nat Sante Rech Med | Derives de 4',4'-dithiobis-(3-aminobutane-1-sulfonate-1- sulfonates) nouveaux et compositions les contenant |
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